# REGULATORS OF EPITHELIAL TUMOR PROGRESSION

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2020 · —

## Abstract

Epithelial tumor progression involves abnormal cell interactions with the extracellular environment as
well abnormalities intrinsic to tumor cells themselves. Cutaneous squamous cell carcinoma (SCC) arises in
skin from ultraviolet mutagenesis and disproportionately affects U.S. Veterans due to sun exposure incurred
in military service. Nationally, SCC is the second most common cancer, with ~1 million new cases yearly.
SCC can lead to disfigurement and, in rare cases, lethal metastases. This Merit Review recently identified
collagens as the most highly mutated gene family in SCC, with the COL11A1 gene the second most
frequently mutated gene overall in SCC (63%). It also found additional collagen genes mutated at high
frequency (>20%) in SCC, including COL17A1 and COL4A4, as well as COL7A1, whose inherited mutation
causes forms of epidermolysis bullosa with aggressive skin SCCs. SCC collagen mutations concentrate at
prolines and glycines in the Gly-X-Y (with X and Y commonly proline) triple helical sequence, alterations
known to produce dominant-negative collagens, raising the possibility that tumor-secreted mutant collagens
may enable cancer in a trans-dominant fashion. Consistent with a pro-oncogenic function for mutant
collagens, knocking in an SCC-associated COL11A1 mutation enhanced neoplastic invasion in vivo
compared to isogenic COL11A1 wild-type control and ablating endogenously mutant COL11A1 in SCC
tumors impaired tumorigenesis in vivo, indicating that mutant collagens functionally promote tumorigenesis.
 Aim I will test a model in which secreted mutant collagen proteins act in a non-cell autonomous fashion
to accelerate tumorigenesis. First, it will determine if mutant COL11A1 can promote neoplastic progression
of tumor cells in trans using mosaic tissue models. Second, it will quantify the impacts on epidermal tumor
progression of mutations in multiple additional collagens that are frequently mutated in SCC, including
COL17A1, COL4A4, and COL7A1. Aim I will study the action of COL11A1 in epidermal tumor progression
and determine if other recurrently mutated collagens can also promote SCC.
 This project also recently used single-cell RNA-sequencing of 47,771 cells from a series of human SCC
tumors, along with patient and site-matched normal control skin, to identify tumor cell subpopulations in
SCC. This defined a new tumor-specific keratinocyte (TSK) population with no counterpart in normal tissue
that expressed COL11A1 and other genes linked to cellular communication and invasion. Such tumor
subpopulations enable neoplasia by communicating with each other through cell surface and secreted
proteins, however, the sets of proteins – as opposed to RNAs – that are actually expressed in living tumors
by specific tumor subpopulations have been a technical challenge to define. To address this, we developed
a new proximity proteomics method, Secreted Protein Identification (SecrID) that can identify cell surface
and secreted proteins within dis...

## Key facts

- **NIH application ID:** 9891608
- **Project number:** 2I01BX001409-09
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** PAUL KHAVARI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2012-01-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891608

## Citation

> US National Institutes of Health, RePORTER application 9891608, REGULATORS OF EPITHELIAL TUMOR PROGRESSION (2I01BX001409-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891608. Licensed CC0.

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