Thread by @whitefishlab

A longstanding question in cancer: why do tumors only form in certain locations in the body? In our new @nature paper (nature.com/articles/s4158…), we define anatomic position of the cell as a mechanism for this.

Led by Josh Weiss (@Joshua_M_Weiss), we found that melanomas that arise in different parts of the body have different DNA alterations. These DNA alterations only cause cancer if they synergize with the intrinsic positional gene program present in these different anatomic sites.

A great News and View summary of the paper written by Marisol Soengas (@msmelanoma) and Chris Marine (@lab_marine): nature.com/articles/d4158…. Thanks to both of you for your insight and perspective.

Acral melanoma, which only arises in the hands and feet, have CRKL amplifications. When Josh modeled this in #zebrafish, he found that the majority of the fish developed tumors in the fins! Why fins?

Because fins are the evolutionary precursors to human limbs, and retain the same positional gene programs as the hands and feet. A great evolutionary connection between fins and limbs was previously shown very elegantly by @NeilShubin and now we see it the cancer context as well.

CRKL synergizes with this positional gene program (dominated by HOX13/IGF signaling) and rapidly transforms those cells. In contrast, cutaneous melanoma, which arises all over the body, have BRAF mutations and the fish developed tumors everywhere.

It is an great example of “oncogenic competence”, which we previously defined (science.org/doi/10.1126/sc…) as a mechanism for why DNA alterations are only transforming in certain contexts.

While one dimension of oncogenic competence is the differentiation state of the cell, here we show that anatomic position is just as important. Cancer formation is a true synergy between the oncogenic DNA alterations plus the pre-existing RNA landscape of the cell.

Aside from just being beautiful basic biology, it also has clinical implications: these anatomic gene programs have unique therapeutic vulnerabilities. The synergy between CRKL and HOX13 makes these cells very vulnerable to PI3K and IGF inhibitors, but not BRAF inhibitors.

It also raises the more general question of whether metastatic tumors could be treated in a site-specific manner, based purely on their anatomic site and accompanying positional gene program? We don’t know the answer to this yet but we want to find out!

This paper is a testament to the sheer perseverance and creativity of the remarkable @Joshua_M_Weiss. He took leadership in all respects on this project and is so deserving of all of his success. He is back in medical school now @TriIMDPhD, and we cannot wait to see his future.

The work was a collaborative effort across many different labs, both here at @MSKCancerCenter and around the world. Within my own lab, a team effort helped by @mrndhntr, @Nelly_M_Cruz, @MohitaTagore, @YilunMa_, @EmilyMontal, @RichardHuang316, @nrcampbell3 and Theresa Simon Vermot

And many other people who contributed to the success of this story: @BaggioliniA, @Sandra_Misale, @JWilmott38, @PeterAJohansson, @ProfGLongMIA, @ProfRScolyerMIA, @BarryTaylorLab, @ChaligneRonan, @PShliaha, @RichardKoche, @studerl, @DSolit, @wolchokj, @merghout, @TeamNicWaddell

Along with Michaelangelo Marasco, Felicity Newell, John Thompson, John Pearson, Graham Mann,
Philip Jonsson, Mark Donoghue, Christopher Harris, Tianhao Xu, Ronald Hendrickson,
Achim Jungbluth, Cecilia Lezcano, Charlotte Ariyan, Neal Rosen, and Nicholas Hayward

Throughout this long process, we could not have done it without the constant support of many funders: @NIH_CommonFund New Innovator Award, @theNCI, the @MelanomaReAlli, @CureMelanoma, the @psscra, @TheMarkFdn, @ACS_Research , @parkerici, and @Ludwig_Cancer