Biology subjects

Coffman, L.

Publications and source records attributed to Coffman, L..

4 recordsLinked to original sources

bioRxiv2026

Breast cancer ovarian metastases show increased activity of GPCR pathways

Treatment resistance and metastases occur in 10-20% of patients with invasive lobular carcinoma (ILC), the most common special histological subtype of breast cancer. ILC metastasizes to the ovary more frequently than no special type (NST) tumors, also known as invasive ductal carcinoma (IDC). To characterize the genomic landscape of breast cancer ovarian metastases, we analyzed 15,613 local breast cancers, 22,010 non-ovarian metastases, and 246 ovarian metastases sequenced using FoundationOne(R)CDx or FoundationOne(R) assays. Ovarian metastases had enriched CDH1, PIK3CA, and TBX3 mutations and depleted TP53 and MYC alterations relative to local breast cancers, with additional depletion of ESR1 mutations compared to non-ovarian metastases. CDH1 mutations were less frequent in ovarian metastases (47%) than local ILC (81.3%), with reduced 16q loss (64% vs 84%), indicating that ovarian metastases also arise from non-ILC tumors. We extended these findings to a UPMC cohort of 27 ovarian metastases (13 ILC, 8 IDC, 6 mixed ductal-lobular carcinoma) with patient-matched primary tumors in most cases. In both cohorts, patients with ovarian metastases were significantly younger than those with other metastatic sites. In the UPMC cohort, the most frequent mutations were in PIK3CA, CDH1, KMT2C, FOXA1, and RUNX1. Transcriptomic analysis identified upregulated G protein-coupled receptor (GPCR) pathways, including metabotropic glutamate receptor signaling. Functional studies showed that calcium-sensing receptor (CaSR), a GPCR overexpressed in ovarian metastases, drives MEK/ERK-dependent migration and F-actin reorganization in ILC cell lines, enhanced by estrogen and blocked by calcilytic, MEK, or anti- estrogen treatment. Our findings inform future therapeutic targeting of ovarian metastasis.

cancer biology↗

bioRxiv2025

Endogenous Nitroalkene Exploits Dependence on Autophagy-Lysosome Pathway in PARPi-Resistant TNBC

Lack of DNA double-strand break repair efficiency exquisitely sensitizes cancers to poly-ADP ribose polymerase inhibitors (PARPi). Unfortunately, resistance to PARPi poses an insurmountable challenge for patients. Mechanisms that confer insensitivity to PARPi therapy include enhanced DNA damage repair and autophagy. Natural and non-natural unsaturated fatty acid nitroalkene derivatives (NFA) show anticancer actions that sensitize TNBC cells to PARPi and other DNA-damaging treatments. We reveal that nitro-oleic acid (OA-NO2) re-sensitizes PARPi-resistant TNBC cells to PARPi. RNA-seq analysis of clinically relevant mutBRCA1 PARPi-resistant TNBC cell lines exhibited upregulation in autophagy and lysosomal pathways. Bio-orthogonal analysis identified the autophagy regulator SQSTM1/p62 as a novel OA-NO2 target, alkylating two redox-sensitive Cys residues of p62 (Cys105 and Cys113). These Cys are essential for p62 regulation of autophagy and mimicked the effects of p62 Cys105 and Cys113Ala mutants and when alkylated by OA-NO2 showed impaired p62 oligomerization, degradation, and inhibition of autophagy. Combination treatment of PARPi-resistant TNBC with a PARPi and OA-NO2 synergistically inhibited p62-associated autophagy and lysosome function. These data emphasize the clinical potential of OA-NO2 for treating PARPi-resistant TNBC patients.

pharmacology and toxicology↗

bioRxiv2023

Alternate splice variants of the mitochondrial fission protein DNM1L/Drp1 regulate mitochondrial dynamics and cell fate in ovarian cancer.

Aberrant mitochondrial fission/fusion dynamics have been reported in cancer cells. While post translational modifications are known regulators of the mitochondrial fission/fusion machinery, we show that alternative splice variants of the fission protein Drp1 (DNM1L) have specific and unique roles in cancer, adding to the complexity of mitochondrial fission/fusion regulation in tumor cells. Ovarian cancer specimens express an alternative splice transcript variant of Drp1 lacking exon 16 of the variable domain, and high expression of this splice variant relative to other transcripts is associated with poor patient outcome. Unlike the full-length variant, expression of Drp1 lacking exon 16 leads to decreased association of Drp1 to mitochondrial fission sites, more fused mitochondrial networks, enhanced respiration, and TCA cycle metabolites, and is associated with a more metastatic phenotype in vitro and in vivo. These pro-tumorigenic effects can also be inhibited by specific siRNA-mediated inhibition of the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the significance of the pathophysiological consequences of Drp1 alternative splicing and divergent functions of Drp1 splice variants, and strongly warrant consideration of Drp1 splicing in future studies.

cancer biology↗

bioRxiv2022

Carcinoma associated mesenchymal stem cells promote ovarian cancer metastasis by increasing tumor heterogeneity through direct mitochondrial transfer

Ovarian cancer is characterized by early, diffuse metastatic spread with most women presenting with extensive abdominal metastasis at the time of diagnosis. Prior work demonstrated carcinoma-associated mesenchymal stem cells (CA-MSCs) enhance ovarian cancer metastasis through a process of direct cellular interaction and formation of heterocellular CA-MSC and tumor cell complexes. In this study, we demonstrated that CA-MSCs enhance metastasis by increasing tumor cell heterogeneity through mitochondrial donation. We showed that CA-MSCs directly interacted with ovarian cancer cells via tunneling nanotubules (TNTs), and CA-MSCs used these TNTs to transfer live mitochondria to adjacent ovarian cancer cells. This mitochondrial donation preferentially occurred with ovarian cancer cells that had the lowest mitochondrial mass, as quantified using live, actively respiring mitochondrial labeling. These mito poor cancer cells demonstrated decreased proliferation, increased sensitivity to chemotherapy, and decreased oxidative phosphorylation compared to mito rich cancer cells. CA-MSCs rescued the phenotypes of mito poor cancer cells, restoring their proliferative capacity, increasing chemotherapy resistance, and increasing oxidative phosphorylation. We validated these findings in a fully autologous system using CA-MSCs and cancer cells derived from the same patient to prevent confounding effects of cellular response to foreign organelle/DNA. Using a knockdown of the mitochondrial motor protein, MIRO1, in CA-MSCs, we demonstrated that mitochondrial transfer is necessary for the CA-MSC-mediated rescue of mito poor cancer cells. Mitochondria of CA-MSC origin persisted in tumor cells over multiple passages. Importantly, CA-MSC mitochondrial donation occurred in vivo, significantly enhanced tumor cell heterogeneity and decreased survival in an orthotopic ovarian cancer mouse model. Collectively, this work identified CA-MSC mitochondrial transfer as a critical mediator of ovarian cancer cell survival, heterogeneity, and metastasis, and blocking CA-MSC mitochondrial transfer represents a unique therapeutic target in ovarian cancer.

cancer biology↗