One abnormal cell is all it takes to kickstart cancer development. The cell acquires genetic mutations and then multiplies uncontrollably into clone cells that share nearly identical genes.
But, according to new research led by Diane Simeone of University of California, San Diego and Aristotelis Tsirigos’ of New York University. these clone cells don't behave like clones in the very aggressive pancreatic ductal adenocarcinoma (PDAC). In a new paper published in Nature Genetics, the researchers used single-cell RNA sequencing on 443,451 cells taken from 65 PDAC tumors, with 11 tumors that also had matched spatial transcriptomics. Their team showed that the clone cells behaved differently from one another, with some edging out others in their ability to resist treatments and some being more likely to spread and metastasize.
“Our work shows that within a single tumor, different clones are evolving in parallel, taking on different identities and interacting with the immune and stromal landscape in distinct ways. That heterogeneity is why the disease is so hard to treat, because every tumor is unique,” said Simeone in the press release.
A single-cell view
The new work offers an unprecedented view into PDAC with the focus on single cells instead of bulk tissue. That allowed the researchers to see for the first time how cancer cells shift between the less aggressive classical subtype and more aggressive basal type with help from the MYC oncogene.
“We showed that there is not a clear distinction between classical and basal pancreatic cancers, but that most tumors are heterogeneous and contain both classical and basal cells intermixed. Phylogenetic trees were created from each tumor, and it appears that classical cells can transition to basal cells in some cases, and requires MYC amplification and immune suppression,” Simeone told DDN.
When the researchers blocked MYC activity, the cells returned to the classical form.
They also found that clone cells were found both in clusters together and dispersed throughout tumors, with the “dispersed cells being the ones that we find to metastasize to regional lymph nodes,” explained Simeone.
Targeted treatments
With this new understanding of clonal heterogeneity and how these cells evolve in PDAC tumors, the scientists are shining a light on how to better design treatments to target them.
“We are now extending this work into analysis of paired biopsies from PDAC patients on Ras inhibitors, to begin to better dissect mechanisms of response/resistance,” said Simeone.
But the work won’t stop there. “The most exciting part of the work is the incredible large data set that is suited to answer a broad array of questions in the field,” she said.
