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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

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April 7, 2011

More Zeroing In On Breast Cancer Cells

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Posted by Derek

While we're on the what's-going-on-inside-cancer-cells topic, there's another new Nature paper that makes interesting reading on the subject. This one also confirms some earlier work, but does a pretty thorough job of it, and sheds some new light as well on that breast cancer mutation work that I blogged about the other day.

This group has taken around 100 cells at a time from tumor samples, and applied single-nucleus sequencing techniques to them. After correcting for a number of factors (see the paper, of course, if you're really into this stuff), they can use this technique to get a good read on the genomic copy number of the cells, which is of particular interest for unstable things like tumor samples. (Comparison of single-cell data versus the averages from samples of millions of cells were also made; the correlations are quite good).

The cells were taken from a breast cancer sample ("triple negative" ductal carcinoma) and from an associated metastatic liver tumor from the same patient. (Given that situation, I'm guessing that these were post-mortem). Each sample was dissected into physical zones, and the cells were then flow-sorted and subjected to sequencing. This revealed a number of interesting patterns.

For one thing, the original tumor sample showed different cell populations across its diameter. There were standard diploid cells in the entire sample, but one population type (less than diploid) was found only one end of the sample, fading out gradually towards the middle, with two other varieties (near-tetraploid) showing up at the other end. On closer inspection, almost all of those garden-variety diploids were normal cells, and most of those were white blood cells, immunocytes that had infiltrated the tumor.

Of the cancer cells themselves, half of them sorted out into three distinct clonal populations, and the metastatic tumor was found to be purely derived one of these. Looking these over, it appears that these three groups emerged very early in the process, and the various mutations (and there were many) still traced back to these early branch points. One of them (arising much later in the process) was clearly more like to break loose and resettle than the others, a pattern that has been seen in other studies. Trying the same thing with another set of tumors from a different patient, they found in this case that the tumor had emerged from a clonal expansion of a single aneuploid cell line, and the metastatic tumor was from one of the later resulting mutants (and had hardly evolved since).

But what about the rest of the tumor cells in these samples? Those turned out to be the pseudodiploid population that they'd seen in the initial sorting, and these were all over the place genetically. No family-tree relationship could be drawn between them (in contrast to aneuploids), indicating that they hadn't been doing the clonal-exapansion thing. They seem to be the result of some ongoing genetic instability in the tumor population, generating a steady stream of one-of-a-kind messed-up cells with missing chunks of chromosomes. You have to wonder if a lot of the 1700 mutations that the full-genome sequencing work picked up were from these cells, and that the other clonally-similar lines showed less variation.

If that's true, it would probably be good news - perhaps all these mutations aren't as evenly spread across the worrisome cells types as you might fear, and especially among the ones that go metastatic. It's a pity that we can't yet do whole-genome sequencing on single nuclei - combining the population breakdown this copy-number technique gives with the hardcore sequence data would really tell the story, and tell us which cells we have to try to kill off first. And finding the root causes of all the genomic instability would be a big advance, too - I wrote about this back in 2002, and it's still relevant and still not well worked out.

Comments (8) + TrackBacks (0) | Category: Cancer


COMMENTS

1. PharmaHeretic on April 7, 2011 9:33 AM writes...

I know this one is about production issues, rather than R&D, but it surely cannot bode well for the public perception of pharma.
---

Johnson & Johnson's Quality Catastrophe

http://www.businessweek.com/magazine/content/11_15/b4223064555570.htm

After 50-plus product recalls in 15 months, the $60 billion company is fighting to clear its once-trusted name

Permalink to Comment

2. Anonymous on April 7, 2011 10:37 AM writes...

"The cells were taken from a breast cancer sample ("triple negative" ductal carcinoma) and from an associated metastatic liver tumor from the same patient. (Given that situation, I'm guessing that these were post-mortem)."

I'd suspect they are not post-mortem but instead mastectomy and axillary lymph node samples removed at the same surgery.

Permalink to Comment

3. Anonymous on April 7, 2011 10:41 AM writes...

Sorry I didn't read carefully and missed the "liver" stuck in there. Could be biopsy still, but may be post-mortem.

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4. Chris on April 7, 2011 11:05 AM writes...

I cant get access to the Nature paper at the moment but id be curious to know if the early mutations were similar to the more common ones seen in the previous study?

Permalink to Comment

5. barry on April 7, 2011 1:42 PM writes...

as sequencing gets cheaper, we may be able to compare cells from a across a single tumor (and a wild-type control) and identify the mutations that they all share. These are likely to be the oldest mutations and therefore most likely to be causal.
I still expect that those will line up with Weinberg's "hallmarks of cancer", plus one more--genetic instability.

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6. PTM on April 7, 2011 10:52 PM writes...

Derek: "You have to wonder if a lot of the 1700 mutations that the full-genome sequencing work picked up were from these cells, and that the other clonally-similar lines showed less variation."

I don't think it's likely. The study that identified those 1700 mutations didn't use single cell sequencing so odd mutations present in only a few cells would likely get washed away and not register at all. The number of identified mutations seems to support this as 1700 in 50 patients is 34 on average per patient.

If 50% of cancer cells had some odd one-of-a-kind mutations and the study was sensitive enough to pick them up the number of mutations identified on average per patient would be way higher then 34.

All this suggests to me that those 1700 mutations were from dominant clonal lines.

Permalink to Comment

7. Cancer Hospital India on April 9, 2011 1:42 AM writes...

Really nice information,

Thank you

Permalink to Comment

8. Bakery on April 9, 2011 1:51 AM writes...

it is a pity that we can't yet do sequencing on single nuclei combining the population technique gives with the hardcore sequence data.

Permalink to Comment

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