bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.10.30.763164

HER3 mediates metabolic reprogramming in metastatic colorectal and pancreatic cancer

Rathore, M.·Wei, C.·Winter, J.·Wang, R.
View original source ↗Export metadata ↓

Abstract

Liver metastases are a major cause of mortality in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), yet the oncogenic signals that shape tumor metabolism in the hepatic niche remain poorly understood. Here, we show that HER3 activation drives a liver metastasis-specific glycolytic program in both cancer types. Genetic or pharmacological HER3 inhibition suppresses cancer glycolysis while increasing dependence on oxidative phosphorylation (OXPHOS), rendering liver metastases vulnerable to OXPHOS inhibition. Combining the HER3 inhibitor sapitinib with distinct OXPHOS inhibitors led to in vitro synergy and durable tumor-free survival in orthotopic CRC and PDAC liver metastases models, with further validation in patient-derived xenografts. Mechanistically, HER3 promotes glycolysis through activating PFK2 and reduces OXPHOS through activating DRP1-mediated mitochondrial remodeling, both pathways were activated in liver metastases compared to matched primary tumors. Together, our findings identify the HER3-AKT/RSK-PFK2 axis as a driver of glycolysis and metastatic growth and reveal an OXPHOS dependency induced by HER3 inhibition that may be exploited through combined HER3 and OXPHOS targeting in metastatic CRC and PDAC.

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Rathore, M., Wei, C., Winter, J., Wang, R.. 2026-11-03. HER3 mediates metabolic reprogramming in metastatic colorectal and pancreatic cancer. https://doi.org/10.64898/2026.10.30.763164

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

A mouse model of metastasis-induced breast cancer cachexia with non-cachectic controls bearing isogenic primary tumors

Background Patients with advanced cancer frequently develop cachexia, an involuntary weight-loss condition that correlates strongly with metastatic burden. Despite this clinical association, metastasis is rarely considered in preclinical research of cancer cachexia, which is in part due to the lack of rigorously established animal models to investigate metastasis-associated cancer cachexia. Methods To establish an animal model of metastasis-associated cancer cachexia, here we focused on syngeneic mouse models of breast cancer. Using the metastatic 4T1 murine breast cancer cell line and its isogenic non-metastatic 67NR cell line, we generated primary tumors via orthotopic injection into the mammary fat pad and surgically resected the primary tumor to allow sufficient time for spontaneous metastatic outgrowth, or generated experimental lung metastases by direct intravenous injection into the tail vein. Across these tumor-bearing groups, we systematically characterized the metastatic burden and cachectic phenotypes of the mice, including body weight, food intake, body composition, muscle mass, grip strength, locomotor activity, energy expenditure, and respiratory exchange ratio. To isolate the contribution of reduced food intake to the cachectic phenotypes, we pair-fed orthotopic 4T1 tumor-bearing mice (which were non-cachectic) to mice with 4T1 lung metastases (which were cachectic). We further measured muscle atrophy gene expression and profiled circulating cytokines and metabolic hormones for the mouse groups. Results Body weight loss occurred exclusively in mice bearing lung metastases from 4T1 tumors, with no weight loss observed in mice bearing either primary 4T1 tumors or 67NR lung tumors, thus presenting a model of cancer cachexia that is driven by 4T1 lung metastasis. Comprehensive cachexia characterization demonstrated that the 4T1 metastasis model recapitulates all key features of cachexia, manifesting as reduced food intake (or anorexia), depletion of adipose tissues, loss of lean mass including muscle mass loss, and reduced grip strength. Pair-feeding non-cachectic primary 4T1 tumor-bearing mice to 4T1 metastatic mice led to the same losses in body weight, fat, and lean mass as in cachectic mice, but no change in grip strength, indicating that anorexia is the primary driver of tissue wasting whereas muscle weakness arises through a food intake-independent mechanism. Moreover, we identified distinct circulating cytokines and metabolic hormones associated with the metastasis-driven cachexia. Conclusions Our results establish a metastasis-induced breast cancer cachexia model with a tightly matched control group, providing a platform for the field to identify metastasis-derived cachectic mediators and pathways.

cancer biology↗
bioRxiv2026

SDHB deficiency silences ABCB1 expression and confers therapeutic vulnerability across multiple cancer types

Succinate dehydrogenase B (SDHB)-deficient cancers, including pheochromocytoma and paraganglioma (PPGL), renal cell carcinoma (RCC), and gastrointestinal stromal tumor (GIST), exhibit aggressive clinical behavior with limited treatment options. To identify novel therapeutic vulnerabilities, we performed high-throughput drug screening using co-cultured human SDHB-deficient and SDHB-reconstituted UOK269 human renal cell carcinoma cells with dual fluorescence labeling. Several compounds displaying preferential cytotoxicity toward SDHB-deficient cells were known substrates of the ATP-binding cassette B1 (ABCB1) transporter, also known as Multidrug Resistance Protein 1 (MDR1). Accordingly, SDHB-deficient cells demonstrated markedly reduced ABCB1 expression, a phenotype confirmed across human SDHB-deficient PPGL, RCC, and GIST samples, but absent in IDH- or FH-deficient tumors. Mechanistic investigation revealed that KDM4A histone demethylase is downregulated in SDHB-deficient tumors, and KDM4A loss (or inhibition) is sufficient to reduce ABCB1 expression, globally increase H3K9me3 levels, and sensitize cells to cytotoxic ABCB1 substrates. TCGA analysis confirmed correlated KDM4A-ABCB1 expression in SDHB-deficient cancers, with ABCB1 levels predicting drug sensitivity across cancer cell lines. Clinical analysis demonstrated that SDHB-mutant PPGL patients treated with vincristine-containing chemotherapy exhibited significantly longer progression-free survival compared to non-SDHB patients. These findings establish a novel metabolic-epigenetic pathway linking SDHB deficiency to ABCB1 silencing and provide rational basis for repurposing vincristine, and related ABCB1 substrate vinca alkaloids, across SDHB-deficient cancer types; offering an alternative precision treatment approach for these challenging malignancies.

cancer biology↗
bioRxiv2026

Polycomb Marked Promoter Methylation Gains in Aging and Cancer are Independent of Replication

DNA methylation alterations are hallmark features of aging and cancer, occurring early during tumor initiation. Yet how these changes evolve during early tumorigenesis, and whether oncogenic signaling actively drives them, remains poorly understood due to limitations in resolving this at the longitudinal and clonal level. Here we developed a genome-wide DNA methylation profiling method for low DNA amounts and applied it to single stem cell-derived clones from a BRAFV600E -inducible mouse colon organoid model, tracking nucleotide-level methylation heterogeneity over time. BRAFV600E induction produced stepwise methylation divergence consistent with progressive clonal takeover, in contrast to gradual epigenetic drift in uninduced controls. Strikingly, while the specific CpG sites altered differed between BRAFV600E and control lineages, they converged on the same genomic elements. Particularly, Polycomb-marked promoter CpG-island methylation gains were not induced or accelerated by BRAFV600E, challenging models in which oncogenic signaling or cell proliferation actively instructs de novo methylation of Polycomb-targeted promoters. Instead, these gains tracked with "biological aging" independent of replication, which was validated across independent aging, cancer, and cell-line datasets. BRAFV600E -induced clones additionally showed progressive loss of intestinal lineage-specification transcription factor programs, consistent with selection for cells adapted to oncogenic stress. Together, these findings show that epigenetic trajectories during early tumor development, are rooted in baseline, age-dependent drivers of epigenetic alterations, and that oncogenic signaling acts primarily by selecting and expanding clones bearing pre-existing, age-associated epigenetic drift rather than instructing new methylation. Our findings have implications for how promoter methylation is interpreted as a cancer biomarker and for identifying upstream aging-associated processes as targets for early intervention.

cancer biology↗