Cancer and Molecular Oncology

The overarching goal of the Cellular and Molecular Oncology (CMO) Research Program is to conduct basic, cancer-relevant research that is focused on discovering the cellular and molecular mechanisms that govern tumor initiation and cancer progression. Our goals are to translate our discoveries into diagnostic and prognostic biomarkers and targets for intervention in clinical and community settings, with a particular emphasis on those cancers with high incidence, mortality, or significant impact in our catchment area.  We use multi-disciplinary approaches that combine sophisticated cell and tissue imaging platforms with computational modeling, and genetic, genomic, and biochemical studies in cell and animal models. These approaches are used to determine the molecular basis for disruption of genome regulation and cell signaling during cancer initiation and progression and the mechanisms by which environmental exposures and other risk factors influence cancer development. Additionally, we identify cancer-promoting mutations and genome-wide mutational signatures resulting from environmental exposures in cancers prevalent in our catchment area and combine the discoveries with studies focused on how these mutations perturb cellular functions, facilitating reverse translation.

The CMO Program has three overall themes that embody its Scientific Aims:

• Aim 1:  Carcinogenic Mechanisms of Environmental Exposures: To discover the molecular and cellular mechanisms by which environmental carcinogens and behavioral risk factors relevant to our catchment area promote cancer. The genetic, genomic, and biochemical processes affected by risk factors (e.g., tobacco use, viruses) and exposures and environmental contaminants, including UV radiation, arsenic, uranium and microplastics, that are prevalent in NM are being studied through the application of cell culture systems, model organisms, and human samples to define novel cellular and molecular mechanisms contributing to cancer and identify potential diagnostic biomarkers.

• Aim 2:  Genome Regulation: To define the mechanisms and pathways by which genome stability, epigenetic alterations, and transcriptional regulation are disrupted in cancer cells. Studies of the genetic, genomic, epigenetic, and biochemical pathways in normal and cancer cells are investigated using cell culture systems, animal models, and model organisms.  Comprehensive genomic approaches are used to define the spectrum of novel cancer-promoting mutations and mutational signatures reflective of genetic factors and environmental exposures in cancers prevalent in our catchment area, particularly in understudied American Indian and Hispanic communities. In turn, CMO members will define how these mutations disrupt normal molecular and cellular functions to promote carcinogenesis.

• Aim 3:  Cellular Signaling and the Tumor Microenvironment: To determine how cell signaling pathways, cellular activities and cell-cell interactions are altered during cancer initiation and progression and within the tumor microenvironment.  CMO members apply innovative spatiotemporal imaging technologies and predictive modeling in normal and cancer cells to discover and dissect the fundamental mechanisms whereby signaling pathways, cellular phenotypes, cell-cell interactions, and the tissue and tumor microenvironment are altered in and contribute to cancer.

Aim 1: Carcinogenic Mechanisms of Environmental Exposures: To discover the molecular and cellular mechanisms by which environmental carcinogens and behavioral risk factors relevant to our catchment area promote cancer.  The effects of environmental exposures on carcinogenesis are the focus of multiple groups in the CMO Program. CMO members Blossom and Hudson serve as deputy director and mentoring director, respectively, on the University of New Mexico Center for Metals in Biology and Medicine (NIGMS P20GM130422) directed by Campen (CCPS). This CoBRE grant supported the research of CMO member early investigators to study the roles of elemental metals in cancers with high prevalence in our catchment area. Progress on these topics resulted in independent NIH R01 funding: Bolt investigated tungsten in breast cancer (R21OH012552; Bolt, Adv Pharmacol 2023;96:119); Xue found iron to play a role in metabolic reprogramming in colon cancer (R01ES035780; Villareal et al. Br J Cancer, 2024; Kao et al. Acta Pharm Sin B. 2024; Arcos et al., Autophagy 2025; details in Aim 3).

Ongoing research on the co-carcinogenic role of arsenic, a metal that is a significant environmental contaminant in NM, and UV radiation (UVR), is supported by a MPI grant to Hudson and Dr. Liu (Stonybrook) to investigate the mutational signatures of this combined environmental exposure (NIEHS R01ES030993). Their work with CMO member Speer and Drs. Zhou (Stonybrook)  and Alexandrov (Moores Cancer Canter) demonstrated that arsenic and UVR co-exposure results in unique gene expression profile that reveals key co-carcinogenic mechanisms (Speer et al. Toxicol. Appl. Pharmacol. 2024; NIEHS R01ES030993). Hudson’s prior preclinical work showing that zinc supplementation reduces the amount of detectable tissue-resident arsenic is being translated to the NM population: interventional clinical trial NCT03908736 will test the potential of supplemental zinc to overcome DNA damage, oxidative stress and inflammation caused by environmental metal exposure in understudied communities. Hudson and CCPS member MacKenzie propose that, as metals share several underlying mechanisms of toxicity that contribute to adverse human health effects, supplemental zinc may mitigate metal toxicity (Hudson et al. Curr. Environ. Health Rep., 2025).

Broad inter-programmatic collaboration is evident in the “UNM Metal Exposure Toxicity Assessment on Tribal Lands in the Southwest (METALS) Superfund Basic Science Research and Training Program” (P42ES025589 PI: Cerrato, CCPS). The NIEHS P30 Center ES032755, “New Mexico Integrative Science Program Incorporating Research in Environmental Sciences (NM-INSPIRES)” is led by CMO members Blossom (Director) and Hudson (Deputy Director) with Campen (CCPS; Director of Professional Development). This Center supports studies on the biological effects of environmental contaminants, including cancer outcomes, in the NM catchment area. CMO member Luo is the director of the Biostatistics and Data Science Core. Though this Center, CMO members In and Castillo worked with CCPS members Campen and Brearley to show that human colon organoids acutely exposed to uranium-bearing dust from a NM site develop a pathophysiological response that shifts epithelial cell lineages, which, in humans, may contribute to gut inflammation and colorectal carcinogenesis (Atanga et al. Environ. Health Perspect. 2024). These and other studies contributed to In’s new NIH funding (NIEHS R01ES034400).

Separately, CMO member Castillo has established UNM as a leader in microplastics research, receiving an NIH R01 (NIEHS R01ES034585) to investigate how environmentally relevant microplastics affect gut health. His collaborative work with In and Campen demonstrated that ingested polystyrene and mixed polymer microspheres accumulate in vivo and alter metabolism in the colon, liver, and brain (Garcia et al., Environ. Health Perspect. 2024). In a complementary human study (Nihart et al., Nature Med. 2025), Campen, Castillo and collaborators applied pyrolysis gas chromatography-mass spectrometry (Py-GC/MS) to quantify micro- and nanoplastics (MNPs) in human autopsy samples from the NM Office of the Medical Investigator, revealing rising MNP accumulation from 2016 to 2024, in the brain, livers and kidneys.  Building on this emerging area, CMO member Xue secured new NIH funding (NIEHS R01ES035780) to define the mechanisms by which microplastics promote colorectal cancer progression, focusing on PIEZO1-mediated oxidative stress and hypoxia-inducible factor 3α (HIF-3α) signaling. Xue’s work integrates experimental models with analyses of archived human colon tissues from individuals in our catchment area, where colorectal cancer incidence is disproportionately high among American Indian and Hispanic populations.

Aim 2:  Genome Regulation: To define the mechanisms and pathways by which genome stability, epigenetic alterations, and transcriptional regulation are disrupted in cancer cells. 

Mao is defining the mechanisms by which DNA damage (e.g., UV photolesions) and DNA repair impact mutation distribution in the cancer genome.  In a recent study, Mao used genome-wide data to show that mutation hotspots at ETS binding sites are correlated with high UV damage formation and low DNA repair rate, but not fast CPD (cyclobutane pyrimidine dimer) deamination in melanoma, which has highest prevalence in non-Hispanic White persons. ETS proteins significantly suppressed CPD deamination by affecting water distribution around the binding motif. Mao found that mutations in the ETS motif in some of the most frequently mutated promoters significantly perturb gene transcription (Duan et al., Proc. Natl. Acad. Sci. 2024). Mao is also working to understand the molecular mechanisms of transcription-coupled nucleotide excision repair (TC-NER), a unique repair pathway dealing with transcription blockage (Hoag et al. Environ, Mol. Mutagen. 2024). He is investigating the hypothesis that the TC-NER initiation factor, Cockayne syndrome B (CSB) protein, binds to DNA damage-arrested RNA Polymerase II (Pol II) and evicts the elongation factor Spt4-Spt5 from Pol II, thereby switching Pol II from transcription to DNA repair (NCI R01CA273458).

Tomkinson continues studies focused on the mechanisms and regulation of DNA replication and repair in non-malignant and cancer cells with the translational goal of developing DNA ligase inhibitors to exploit abnormalities in DNA replication and repair in cancer cells. On-going studies with Dr. van Houten (University of Pittsburgh) examining the different effects of inhibiting mitochondrial DNA ligase 3 (Lig3) on mitochondrial function in cancer and non-malignant cells formed the basis of a successful grant renewal (NIEHS R01ES012512-19, Tomkinson PI) with CMO member collaborator Mandell. Previously, in collaboration with Dr. Madhusudan (University of Nottingham), Tomkinson identified DNA ligase I (LigI) as a prognostic indicator and a potential therapeutic target in ovarian cancer. Given the well-established role of Lig1 in DNA replication, Tomkinson has examined the effects of genetic and chemical induced LigI deficiency. Recently, his group investigated for the first time the roles of PARP1 and PARP2 in this pathway. They found that PARP1 and PARP2 have a redundant essential role in LigI-deficient cells. Their results suggest that PARP2 plays a major role in specific cell types that are more dependent upon the backup pathway to complete DNA replication and that PARP2 retention at unligated Okazaki fragments likely contributes to the side effects of current clinical PARP inhibitors (Bhandari et al., Nucleic Acids Res. 2024).  Tomkinson collaborated with Dr. Shan Zha (Herbert Irving Comprehensive Cancer Center) to show that inactive PARP2, but not its active form or absence, impedes LigI- and LigIII-mediated ligation, causing replication fork collapse in erythroblasts with ultra-fast forks. This PARylation-dependent structural function of PARP2 at 5' p-nicks explains the detrimental effects of PARP2 inactivation on erythropoiesis, shedding light on PARPi-induced anemia and the selection for TP53/CHK2 loss (Lin et al. Mol. Cell 2024). An NCI grant (R01CA276837) with co-I Leslie (CT) and CMO member Steinkamp is evaluating the activity of LigI inhibitors in ovarian cancer. Tomkinson is a co-investigator on a DoD grant (W81XWH2210754) led by Leslie (CT) to determine the effects of p53 reactivation in advanced endometrial cancer.

Fan and Lake study epigenetic regulation, including how chromatin structure is regulated by energy-dependent chromatin structure regulators and transcription factors, and how defects in these proteins contribute to carcinogenesis.  Fan and Lake collaborated with Tomkinson to report novel insights into how the Cockayne syndrome protein B (CSB), an ATP-dependent chromatin remodeler, collaborates with PARP1 in the repair of oxidative DNA lesions.  They showed that PARP1 and PARP2 promote recruitment of CSB to oxidatively damaged DNA. CSB, in turn, contributes to the recruitment of XRCC1, and histone PARylation factor 1 (HPF1), and promotes histone PARylation to regulate single strand break repair (SSBR) mediated by PARP1 and PARP2. Their work indicates that CSB-mediated SSBR occurs primarily at actively transcribed DNA regions, raising the possibility that SSBR is executed by different mechanisms based on the transcription status (Bilkis et al., Cells. 2025). The Fan and Lake team also found that that the FDA-approved drug Auranofin is a potent Notch pathway inhibitor that synergizes with cisplatin. They leveraged NCI funding (R21CA286210) and CCC pilot awards to test the utility of Auranofin and cisplatin cotreatment for targeted ovarian cancer therapy and received new DoD funding to extend this work in collaboration with CT member Leslie and CMO member Steinkamp (DOD HT9425-24-1-0736). This project will employ a variety of preclinical models, including Steinkamp’s humanized mouse model (HuNBSGW; see Aim 3), wherein they will strive to improve targeted ovarian cancer therapy using Auranofin.

Palanisamy studies RNA-binding proteins (RPBs) and their contribution to gene expression patterns in oral cancer models. Specifically, this work has provided significant advances in understanding the molecular functions of RBPs HuR and FXR1 and their role in oral epithelial homeostasis and cancer progression. His recent study found that transgenic HuR knockout (KO) mice developed significantly smaller oral tumors in a carcinogen induced cancer model. HuR-KO tumors showed fewer CD4+CD25+FoxP3+ regulatory T cells, more CD8+ T cells suggesting that HuR dampens the immune response during oral cancer progression.  HuR KO animals had fewer Tregs and higher IFN levels than WT tumor-bearing mice, indicating HuR has anticancer activities. Finally, the HuR inhibitor pyrvinium pamoate reduced tumor burden by increasing CD8+ infiltration over CD4+, suggesting HuR inhibitors should be investigated as a novel HNSCC treatment (Majumder et al., Oral Oncol Rep. 2024). Palanisamy also found that the protein methyltransferase PRMT5 plays a role in the processing of arginine methylation of RNA-binding protein, FXR1, which in turn increases its RNA-binding ability. The process of R-methylation enhances the stability of the FXR1 and facilitates gene expression in oral cancer cells (Vijayakumar et al., Nucleic Acids Res. 2024). This work provides novel insight into how a network of RBPs mediates post-transcriptional gene activity that participates in biological functions and targets mRNA, miRNA, long non-coding RNA, and proteins. Notably, silencing FXR1 leads to reduced oral tumors and enhanced immune responses in solid oral tumors indicating that FXR1 might be a therapeutic target for immune “cold” oral tumors (NIDCR R01DE030013-06; R21DE032461).

CMO member Vue studies the genetic mechanisms that regulate the hierarchy and heterogeneity of tumor cells in glioblastoma (GBM), the most common and malignant form of glioma. Despite the use of fluorescence-guided surgery for maximal tumor resection followed by concurrent chemotherapy with temozolomide (TMZ) and conformal radiation, recurrence is unavoidable as it is not possible to eliminate all malignant cells. The limited efficacy of chemoradiation is also attributed to the heterogeneity and plasticity of GBM cells.  Collaborating with Drs. Borromeo and Johnson (Simmons Comprehensive Cancer Center), the Vue team utilized a majority of the UNM CCC’s Shared Resources to study the dysregulation of the basic-helix-loop-helix (bHLH) transcription factors that are dynamically and highly co-expressed in GBM. They found that the binding of ASCL1 and OLIG2 to each other’s loci and to downstream target genes determines the cell types and degree of migration of tumor cells. Single-cell RNA sequencing (scRNA-seq) revealed that a high level of ASCL1 is key in specifying highly migratory neural stem cell astrocyte-like tumor cell types, which are marked by upregulation of ribosomal protein, oxidative phosphorylation, cancer metastasis, and therapeutic resistance genes.  Together their results show a pivotal role for ASCL1 as a master regulator of genes essential to sustain the highly proliferative, migratory, and therapeutic-resistant potential of astrocyte-like glioma stem cells within GBM tumors in the brain, which reveals new potential therapeutic targets for treating GMB (Myers et al. Nat. Commun. 2024; NINDS R01NS121660; ACS-IRG-21-146-25-IRG, CCC pilot funding).

Aim 3:  Cellular Signaling and the Tumor Microenvironment: To determine how cell signaling pathways, cellular activities and cell-cell interactions are altered during cancer initiation and progression and within the tumor microenvironment. 

D. Lidke uses high-resolution microscopy and single molecule tracking with biophysical and functional read-outs to interrogate the molecular mechanisms of signaling by receptor tyrosine kinases and immunoreceptors (D. Lidke and Low-Nam Biophys. J. 2024).  Collaborative efforts between the groups of D. Lidke, K. Lidke (CMO) and Dr. Lemmon (Co-Director, Yale Cancer Biology Institute) used single molecule imaging to gain new understanding of the structural requirements of epidermal growth factor receptor (EGFR) interactions.  They showed that higher-order EGFR assemblies are involved in EGF-induced signaling, which may have implications for treating cancers with EGFR mutation or overexpression (Mudumbi et al., Cell Reports 2024).  D. Lidke also worked with Dr. Lakin (UNM Biomedical Engineering) to address the challenge that oligonucleotide therapeutics, many of which are FDA-approved for sera and treatments, are subject to degradation by exogenous nucleases. They used naturally degradation resistant l-DNA to produce heterochiral oligonucleotides and reported that multiple nucleic acids can be transfected into human cells and subsequently undergo interactions that persist for over 18 hr. This work advances the state of the art of l-nucleic acid protection of oligonucleotides and DNA circuitry for in vivo applications including enabling “smart” oligonucleotide therapeutics that can autonomously sense and respond to a disease state (Mallette et al., Chembiochem 2024).

CMO member Ozbun studies human papillomavirus (HPV) infections that can lead to cancers of the cervix, anus, vagina, and oropharynx.  HPV inoculation rates in NM remain well below (50.3-61.9%) the WHO’s 90% benchmark for world-wide cervical cancer elimination, and NM American Indian women are less likely to be screened for cervical cancer compared to other women in our catchment area.  Ozbun continues a collaboration with CMO member Kang, McConville (CT), and Dr. Spurgeon (Carbone CCC) to formulate and evaluate the efficacy of topical FDA-approved MEK signaling inhibitors that promote neoplastic reversion in HPV tissue models and promote tumor regression in mouse models of HPV disease (NIAID R21AI176571). Leveraging data from prior studies. CCC pilot grants, and the R21 funding, Ozbun received a new NCI R01 (R01CA293012) to determine the mechanisms of papillomavirus tumor regression by MEK inhibition in collaboration with CMO members Kang, Edwards, Castillo, and CT member Bartee. Preliminary data from these projects are promising and a next step will be seeking an FDA investigational new drug approval for IITs aimed to treat patients with HPV-induced precancers. Working with Drs. Traina-Dorge and Datta at the Tulane National Primate Research Center, Ozbun was awarded an NIDCR grant (R21DE033875) to establish a Rhesus macaque model of persistent oral HPV and HIV co-infection to study oropharyngeal cancer induction.

Marchetti’s research program focuses on discovering biomarkers related to and mechanisms underlying cancer metastasis. His group investigates the fundamental biology of circulating tumor cells (CTCs), the “seeds” of fatal metastasis, isolated from patients with breast cancer (a cancer with highest prevalence in our catchment area) and melanoma (with highest prevalence in non-Hispanic Whites). Marchetti’s group has been building on their important finding that melanoma brain metastasis (MBM)-competent CTCs possess a unique gene signature, the “CTC RPL/RPS gene signature,” where RPL/RPS refers to ribosomal proteins of the large and small subunit, respectively; this gene signature is directly related to the onset of MBM (Bowley and Marchetti, Clin Exp Metastasis 2024). They tested the hypothesis that CTC-driven MBM secondary metastasis (“metastasis of metastasis” per the clinical scenarios) has targeted organ specificity for the liver.  Working with CMO member Steinkamp, and CT members Fahy, Harai-Turquie, and Tawfik, they injected parallel cohorts of immuno-deficient and newly developed humanized mice (HuNBSGW) with cells from CTC-derived MBM to identify secondary metastatic patterns. The team discovered the presence of a melanoma brain-liver metastasis axis in the humanized NBSGW mice. RNA-seq analyses of tissues showed a significant upregulation of the RPL/RPS CTC gene signature linked to metastatic spread to liver. Additionally, RNA-seq of CTCs isolated from HuNBSGW blood revealed extensive CTC clustering with human B cells in these mice. CTC:B cell clusters were also at increased levels in blood from primary melanoma patients and were maintained either in CTC-driven MBM or MBM CTC-derived cells promoting liver metastasis. CTC-generated tumor tissues interrogated at the single cell level using 10x Genomics’ Xenium technology showed that heterotypic CTC:B cell interactions are found at multiple stages of metastasis. This work provides important insights for the relevance of pro-metastatic CTC:B cell clusters extending from primary metastatic disease and identify new targets for clinical metastasis to improve patient care (Bowley et al. Cancer Res Comm 2025).

CMO member Steinkamp collaborated with CMO members Hudson, Ness, and Wandinger-Ness, along with Pankratz (CCPS) and Adams (CT), to report that humanized mice (HuNBSGW) engrafted with human CD34+ cord blood-derived hematopoietic stem cells and bearing patient-derived xenografts (PDXs) establish an immune tumor microenvironment like that reported for patients with ovarian cancer. This humanized model supports PDX growth that retains the genetic heterogeneity of the primary tumor and exemplifies the original tumor morphology with the added advantage of creating an immune tumor microenvironment containing human myeloid and T cell infiltration. Thus, the humanized mouse model facilitates more clinically relevant investigations of immune cell recruitment, cancer cell/immune cell interactions, and novel therapeutics. Steinkamp obtained new funding using this model in an NCI Supplement (5P50CA265793-02W1) to the Route 66 Endometrial Cancer SPORE to study autologous humanized mouse models of endometrial cancer in which the immune cells are differentiated from induced pluripotent stem cells derived from the same patient. For this project she is collaborating with Drs. Mutch (Wash. U), Sturgeon (Mt. Sinai) and Leslie (CT). Steinkamp is co-I on a DoD grant "Advancing Clinical Research in Ovarian Cancer" with PI Adams (CT) and Sahu (CT) that established a pipeline for clinical trials aimed to identify a target population for new therapies using AI-based predictive software validated using patient-derived organoid and PDX models. Co-PIs Steinkamp and Sahu (CT) also received a three-year Oxnard Foundation grant to test alternative personalized therapies for platinum-resistant ovarian cancer patients using transcriptome analysis and PDX models to validate response.   Humanized PDX models are being utilized by Serda (CT) in collaborative NCI grants (R21CA282618, R01CA293942) with Steinkamp as co-I to test silicified cancer cell sera.  For these projects, the Animal Models Shared Resource engrafts HSPCs into immunocompromised mice that express the human HLA-A 2.1 allele to allow for more natural maturation and activation of CD8+ T cells.  Steinkamp is a co-I on a P01 (P01CA278735-01A1) that received a fundable score (impact score 27) in collaboration with Leslie (CT) and Dr. Thiel (Holden CCC), "Advancing Hormone Therapy for Endometrial Cancer" that will use humanized endometrial cancer PDX models to determine the effect of progestins on the tumor immune microenvironment.

Xue is also defining the mechanisms whereby the micronutrient iron impacts gastrointestinal inflammation and colon cancer. Xue demonstrated that reduced iron transport and lower mitochondrial iron accumulation results in decreased colon tumor cell growth in vitro and in vivo, indicating that therapies aimed to reduce mitochondrial iron levels may effectively inhibit colon tumor growth (Kao et al. Acta Pharm Sin B. 2024; Arcos et al., Autophagy 2025). Xue’s lab also reported that HIF-3α1 plays a critical role in colon cancer progression by promoting EMT, iron accumulation, and metastasis through ZEB2 and TFRC regulation, suggesting potential therapeutic targets in colorectal cancer (Villareal et al. Br J Cancer, 2024).  Xue was awarded UNMCCC Translational Science Initiative pilot funding with Brown-Glaberman (CT) to analyze tumor iron distribution and biomarkers in archival colon cancer biopsy specimens. The goal is to obtain feasibility data to support a window of opportunity trial that will investigate the impact of iron chelators on CRC patients.