Siddhartha Mukherjee

MUKHERJEE,  Siddhartha, Cancer,  Columbia, May 8, 2018

SM = Sid. Mukherjee is a prof at Columbia.

This is an oncology seminar at Stanford in Berg Hall at 3PM today, May 8, 2018.

Intro by Prof. Irv Weissman.  SM was an undergrad at Stfd.

SM begins...

He shows the famous  New Yorker cartoon showing the

Hudson River and a thin band of New Jersey and then Calif and Pacific Ocean...

basically with nothing in between.

he superimposed on that map..  Cancer as New York City and the

Genome and  then way way far off... Cells and the microenvironment.

yes, perhaps  we're missing the organismal  aspects that are influential.

perhaps missing the big picture (of the human environment and cell microenviro.)

outline for today:

the identity of a novel skeletal stem cell and its

implications for osteoarthritis and bone metastatic cancer

and chemo-nutritional therapy for cancer

and cell immunotherapy for myeloid leukemias...

he begins topic one above on anatomy of bone...

he shows the growth plate and articular surface...

eg  tibial  plateau's articular surface...

cartilage cells on top  in the proliferative zone

and then fibrocartilage zone

and then calcified cartilage.

and then the long bone:  with no cartilage;  and surrounded by periosteum.

so,  how does cartilage grow...

signals btwn  bone and bone marrow... will not talk about that.

what follows is in mouse models... using RNA seq.

GREMLIN-1  ID'd by RNA seq of bulk cells.

this is Worthley in Cell 2014...

we made transgenic mice...

both  Grem-1  Cre and Grem1 GFP.

we found that Nestin cells and Gremlin + cells are distinct.

he shows CFUs = colony forming units.

we isolated Grem+ cells  (they form  cartilage islands)

they express genes that are known to form  in cartilage cells.

so,  Gremlin1 cells form  bone scaffold.

if you stain, you see articular surface and periarticular area.

the stromal cells are down below  (toward the long bone) and those

cells may interdigitate but never transform or mix.

now, say,  pulse...  that is... turn gremlin-1 on at P3 in this mouse.

it turns on everything...many cell lines are turned on.

so,  GREMLIN-1  idntifies a skeletal stem cell.

and these are totally distinct from "mesenchymal stem cells"  (which are Nestin+)

so,  where do these skeletal stem cells live?

answer... inside the bone  but also on the articular surface of the bone...

adult bone is formed from the growth plate and from the artic surface (and other)

do these articular  osteocyte progenitor cells  (defined by Gremlin1+)

self-renew?  and then  what is their fate?

he shows  trace at 25 weeks (in this mouse model)

these stem cells live in the so-called junk layer

 (btwn surface cartilage and (below) toward the long bone)

Sean Morrison  pub  Zhou and Morrison in Cell Stem Cell in 2014...

another former  Irv grad student.

(these are LEP-R + cells.

Gremlin1 + cells  are in the growth plate and in artic surface and in periosteum.

and come on early.

in contrast  LEP-R+ cells  just make  osteocytes  to maintain and repair long bone fractures.

the role of  Gremlin1+ cells is to .... create artic surface and bone cuff, and they make

osteoblast, and reticular cells and chondrocytes  = OCR =

osetocytes, chondrocytes, and reticular cells.

and grem+ makes  ligaments.

so, we ID'  a new stem cell and want to quantify who contributes what and when with

Grem+  versus  LEP-R+ cells. to bone and cartilage.

shows pic of oseoarthritis...  v  bad  hands...

enormous disease burden.

OA has a propensity in women.

he shows  normal knee vs  a knee with OA.

but do not see much of a difference.

but huge diff. when you look at Grem+ cells.

could be that OA is a progenitor cell problem

(b/c they are almost gone!)

we want to see if we can promote cartilage differentiation in knees.

some desperate people go to Puerto Vallarta. to get  stem cell injection...

the only good part is the vacation in Mexico.

several 100M  dollar industry.

we look at shaved off artic surface for arthroscopy...

and label this...

we see single cell  Grem+ cells.

(classical :  take bone marrow and then get mesenchymal fibroblasts

(but those are the wrong cells to make cartilage)

next topic:  metabolic therapy of cancer...

collab with Lew Cantley...

we know almost nothing abt the role of diet in cancer...

he works on leukemia and MDS = myelodysplasia syndrome.

what is role of  PI3 kinase inhibitors in breast CA.

negative study... no benefit from pictilisib... from early 2000s.

pron picTILL isib.   but they get hyperglycemia... only become diabetic.

seems that PI3K inhibitors cause spikes in blood glucose in human patients.

seems that insulin restores signaling and growth in PI3

then we looked at models of insulin feedback caused by PI3Ki .

how to lower blood glucose...

we tried a ketogenic diet; and metformin; and SGLT2i and compared

to normal chow (in rodents)

most effective was the ketogenic diet !!!

seems that ketogenic diet synergyzes with BKM120 in eight different tumor models.

he shows disappearance of mouse tumors.

but KETO DIET alone  ACCELERATES the CA!!!

(this only works if patient is also getting BKM120.

we are starting a trials planned for 2018.

Maethades Therapeutics will create  KETO/PI3K  therapies.

  last story *

Immune therapy for Myeloid leukemia....

problem eg  for direct  CAR-T therapy for myeloid leukemia.

you can live w/o b-cells

in ALL, CD19 and CD20 are b-lineage antigens.

however in myeloid lekemia, lineage antigens are shared with myeloid cells

(including  HSCs = hematopoietic stem cells)

so,  cannot suppress AML w/o  clobbering the HSCs.

so,  why not make a tumor  antigen...

eg  make  HSCs that are  CD33 negative... and infuse...

cuz won't get an attack on them.

(say,  do that with CRISPR)

seems that  CD33 deletion in CD34+ cells does not impair

 their normal growth and differentiation.

Siddhartha Mukherjee

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