bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.11.01.763528

Coupled Modeling of Tumor Volume and ctDNA Dynamics in HPV-Associated Anal Squamous Cell Carcinoma

Havor, P. M.·Huffman, B. M.·Cleary, J. M.·Jabalee, J.·Brady-Nicholls, R.
View original source ↗Export metadata ↓

Abstract

Response to anti-PD-1 immunotherapy in advanced HPV-associated anal squamous cell carcinoma (ASCC) varies and is assessed by infrequent imaging that lags behind tumor biology. Circulating tumor DNA (ctDNA) can be sampled frequently and reflects near-real-time tumor activity yet is rarely built into mechanistic models of treatment response. Using longitudinal tumor volume and HPV ctDNA from 26 patients treated with pembrolizumab, we found that baseline ctDNA scores tracked tumor burden but did not distinguish responders from non-responders, whereas ctDNA after one treatment cycle had a higher relative decrease in responders, six weeks before the next scan. We developed an ordinary differential equation model linking tumor volume to the ctDNA released by tumor cells. Sensitivity, identifiability, and model-selection analyses reduced it to two patient-specific parameters, proliferation and shedding rates, which reproduced individual volume and ctDNA trajectories, including a transient ctDNA spike at treatment onset. Proliferation was faster in non-responders. This framework supports model-based, ctDNA-guided monitoring of immunotherapy response.

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Havor, P. M., Huffman, B. M., Cleary, J. M., Jabalee, J., Brady-Nicholls, R.. 2026-11-03. Coupled Modeling of Tumor Volume and ctDNA Dynamics in HPV-Associated Anal Squamous Cell Carcinoma. https://doi.org/10.64898/2026.11.01.763528

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

KEEP EXPLORING

Related preprints

bioRxiv2026

Adaptation of breast cancer cells to serum-free defined medium reveals changes in proliferation, adhesion, and lipid metabolism

Cancer cell metabolic dependencies are strongly influenced by nutrient availability, yet conventional culture conditions contain non-physiological nutrient concentrations and poorly defined serum components that may obscure metabolic vulnerabilities. Here, we investigated the adaptation of three breast cancer cell lines to physiologically relevant, serum-free defined medium (DM). Using a stepwise reduction in fetal bovine serum (FBS), we evaluated proliferation, adhesion, morphology, and transcriptional changes in HER2-positive SK-BR-3, triple-negative MDA-MB-231, and ER-positive/HER2-positive BT-474 cells. The three cell lines differed substantially in their ability to adapt to serum-free conditions. MDA-MB-231 cells adapted readily, maintaining proliferation and adhesion without exogenous substrate coatings. SK-BR-3 cells also achieved sustained proliferation in serum-free DM, but required a serum-derived coating to maintain adhesion. In contrast, BT-474 cells failed to sustain adhesion and proliferation following complete serum withdrawal, although they remained proliferative in medium containing 1% FBS. Adapted cells retained characteristic HER2 or vimentin expression despite changes in morphology and proliferation. RNA sequencing revealed extensive transcriptional remodeling, including reduced expression of cell-cycle-associated programs in SK-BR-3 cells and enrichment of cholesterol homeostasis gene sets in SK-BR-3 and MDA-MB-231 cells. Expression of cholesterol regulatory genes, including SREBF2, HMGCR, and LDLR, increased across all three lines. Together, these findings highlight cell-line-specific adhesion requirements and shared metabolic responses to serum withdrawal, establishing a framework for developing defined culture systems to investigate cancer metabolic dependencies through genetic screening.

cancer biology↗
bioRxiv2026

Lineage tracing in rhabdoid tumor organoids and orthotopic xenografts reveals convergent transcriptional states

Malignant rhabdoid tumors (MRTs) are aggressive pediatric malignancies driven by loss of a single SWI/SNF subunit in an otherwise near-silent genome, yet they display extensive transcriptional heterogeneity. Whether this heterogeneity reflects the outgrowth of transcriptionally distinct clones, or states adopted independently of lineage, is unknown. Here we combined lentiviral lineage barcoding with single-cell RNA sequencing in two patient-derived renal MRT organoid models, followed through long-term in vitro culture and in a novel orthotopic xenograft setting. In both modalities, tumors and cultures became progressively restricted to a small number of lineages, and the clones that expanded were transcriptionally distinct from one another. Decomposing into gene expression programs showed that some transcriptional states were used broadly across lineages while others were confined to a few, and that lineages expanding independently, in separate cultures and separate animals, converged on the same restricted states. Individual lineages generally maintained their transcriptional identity across passaging and across anatomical sites, including in metastases, which arose from clones already expanded in the matched primary tumor. Which lineages came to dominate, however, differed between animals given the same starting population. Clonal outcome is therefore variable while the transcriptional states available to a tumor are drawn from a constrained and recurring repertoire.

cancer biology↗
bioRxiv2026

The Pregnane X Receptor (PXR) contributes to phenotypic plasticity and modulates the sensitivity to targeted therapies in melanoma

The challenge in treating advanced metastatic melanoma lies in the development of therapeutic resistance and the risk of recurrence. Understanding the mechanisms underlying tumor adaptation to treatment is therefore crucial, as they can directly influence therapeutic efficacy. Tolerance to targeted therapies may be influenced by drug transport and metabolism within tumors, processes regulated by numerous genes under the transcriptional control of the nuclear receptor PXR (Pregnane X Receptor, NR1I2). We revealed, for the first time, significant and heterogeneous expression of PXR in human melanoma samples. We previously showed that PXR can be activated by BRAF inhibitors (BRAFi), but not by MEK inhibitors (MEKi), which are currently used in combination for the treatment of BRAF-V600E-mutated melanoma. Here, we investigated whether PXR expression influences melanoma cell sensitivity to MAPK pathway inhibitors. Using BRAF-mutated human melanoma cell lines, we showed that stable PXR expression sensitizes cells to combined BRAFi/MEKi treatment. Transcriptomic analysis further revealed that PXR expression is associated with the upregulation of several phenotypic markers, with MITF identified as a major regulator in untreated PXR-overexpressing cells. These findings suggest that PXR promotes a shift toward a melanocytic phenotype, which is associated with increased sensitivity to BRAFi/MEKi treatment. Characterization of the PXR-associated transcriptional signature in melanoma may therefore have translational value for identifying patients more likely to benefit from targeted therapies and support the development of PXR as a predictive biomarker of therapeutic response.

cancer biology↗